School of Medicine and Pharmacology, Harry Perkins Institute and School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia, Australia.
Department of Immunology, Sir Charles Gairdner Hospital and Pathwest, Crawley, Western Australia, Australia.
Sci Rep. 2018 May 8;8(1):7224. doi: 10.1038/s41598-018-25559-6.
Hepatitis C virus (HCV)-specific T cell responses are critical for immune control of infection. Viral adaptation to these responses, via mutations within regions of the virus targeted by CD8 T cells, is associated with viral persistence. However, identifying viral adaptation to HCV-specific CD4 T cell responses has been difficult although key to understanding anti-HCV immunity. In this context, HCV sequence and host genotype from a single source HCV genotype 1B cohort (n = 63) were analyzed to identify viral changes associated with specific human leucocyte antigen (HLA) class II alleles, as these variable host molecules determine the set of viral peptides presented to CD4 T cells. Eight sites across the HCV genome were associated with HLA class II alleles implicated in infection outcome in this cohort (p ≤ 0.01; Fisher's exact test). We extended this analysis to chronic HCV infection (n = 351) for the common genotypes 1A and 3A. Variation at 38 sites across the HCV genome were associated with specific HLA class II alleles with no overlap between genotypes, suggestive of genotype-specific T cell targets, which has important implications for vaccine design. Here we show evidence of HCV adaptation to HLA class II-restricted CD4 T cell pressure across the HCV genome in chronic HCV infection without a priori knowledge of CD4 T cell epitopes.
丙型肝炎病毒 (HCV)-特异性 T 细胞应答对于感染的免疫控制至关重要。病毒通过在 CD8 T 细胞靶向的病毒区域内发生突变来适应这些应答，这与病毒持续存在相关。然而，尽管了解抗 HCV 免疫至关重要，但识别 HCV 特异性 CD4 T 细胞应答的病毒适应性一直很困难。在这种情况下，对来自单一 HCV 基因型 1B 队列（n = 63）的 HCV 序列和宿主基因型进行了分析，以鉴定与特定人类白细胞抗原（HLA）II 类等位基因相关的病毒变化，因为这些可变宿主分子决定了呈递给 CD4 T 细胞的病毒肽集。在该队列中，与感染结局相关的 HLA II 类等位基因共鉴定到 HCV 基因组上的 8 个位点（p ≤ 0.01；Fisher 确切检验）。我们将此分析扩展到慢性 HCV 感染（n = 351）的常见基因型 1A 和 3A。HCV 基因组上 38 个位点的变异与特定的 HLA II 类等位基因相关，不同基因型之间没有重叠，提示存在基因型特异性的 T 细胞靶标，这对疫苗设计具有重要意义。在这里，我们在没有预先了解 CD4 T 细胞表位的情况下，在慢性 HCV 感染中显示了 HCV 对 HLA II 类限制的 CD4 T 细胞压力的全基因组适应的证据。
